Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors

  • Bioorg Med Chem Lett. 2009 Jan 1;19(1):21-6. doi: 10.1016/j.bmcl.2008.11.023.
Kirk L Stevens  1 ,  Krystal J Alligood ,  Jennifer G Badiang Alberti ,  Thomas R Caferro ,  Stanley D Chamberlain ,  Scott H Dickerson ,  Hamilton D Dickson ,  Holly K Emerson ,  Robert J Griffin ,  Robert D Hubbard ,  Barry R Keith ,  Robert J Mullin ,  Kimberly G Petrov ,  Roseanne M Gerding ,  Michael J Reno ,  Tara R Rheault ,  David W Rusnak ,  Douglas M Sammond ,  Stephon C Smith ,  David E Uehling ,  Alex G Waterson ,  Edgar R Wood
Affiliations
  • 1. Department of Oncology Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. [email protected]
PMID: 19028424 DOI: 10.1016/j.bmcl.2008.11.023
Abstract

A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 Receptor Tyrosine Kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.